# IRI, innate immunity and transplant rejection

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $463,436

## Abstract

Project Summary/Abstract
Organ transplantation is a critical therapy for patients with irreversible organ damage. Short-term outcomes are
excellent, but most patients lose their organs eventually due to chronic immune-mediated injury over time.
Ischemia reperfusion injury (IRI) is unavoidable in transplantation and the primary activator of the innate
immune response in the early post-transplant period, which enhances the rates of acute and chronic allograft
rejection subsequently. Furthermore, a critical worldwide shortage of organs available for transplant exists,
which has prompted clinicians to use organs from donors who are older or have greater comorbidity. These
organs have much greater susceptibility to ischemic injuries. Therefore, the association of IRI with increased
allograft immunogenicity has very broad clinical implications. Costimulatory blockade (CB) has emerged
recently as a highly promising therapeutic approach in transplantation with far superior microvascular and
metabolic safety profile than calcineurin inhibitors. However, CB is associated with increased rates of acute
allograft rejection during the early post-transplantation phase. Our data indicate that IRI abrogates the
tolerogenic effect of CB. Therefore, a key unmet need in transplantation is to understand better the
mechanisms by which IRI and its activation of the innate immune response potentiates transplant rejection, as
novel therapeutic regimens to prevent or ameliorate IRI-induced alloimmunity could assist in reducing chronic
rejection. Our main goal is to reveal the underlying mechanisms of augmentation of transplant rejection by IRI.
Pursuant to our data, our main hypothesis is that IRI activates alloimmunity by A) increasing the early intra-
graft inflammatory response and B) priming the draining lymph node (DLN) of the graft recipient through
distinctive microanatomical changes. We have shown that early intra-graft inflammatory responses play a
critical role in augmenting alloimmunity. We also propose here for the first-time the use of nanoparticles for
targeted delivery of immune therapeutics to the DLN for the reduction of IRI-induced alloimmunity. In AIM 1,
we will examine how induction of autophagy in donor dendritic cells by IRI creates a pro-inflammatory milieu
within the organs that augments alloimmunity. In AIM 2, we will examine the mechanism by which IRI of the
grafts primes the DLN microanatomically to amplify the alloimmune response. In AIM 3, we will develop
nanoparticles for the targeted delivery of CB to the DLN for augmentation of their tolerogenic effects in
reducing the deleterious effects of IRI.

## Key facts

- **NIH application ID:** 10107424
- **Project number:** 1R01AI156084-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Reza Abdi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,436
- **Award type:** 1
- **Project period:** 2021-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107424

## Citation

> US National Institutes of Health, RePORTER application 10107424, IRI, innate immunity and transplant rejection (1R01AI156084-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107424. Licensed CC0.

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